Compounds and their therapeutic use

ABSTRACT

Compounds of formula I:  
                 
 
     [wherein:  
     X represents —CH═CH—, —CH═CR—, —CR═CR—, —CO—, —O—, —NH—, —NR—, S—, —SO—, —SO 2 —, —CH═N—, —CR═N—, —CH═N(O)—, —CR═N(O)— or any other atom or group of atoms capable of forming a S— or 6-membered heterocyclic ring;  
     Y 1 , Y 2  and Y 3  independently represent hydrogen or halogen;  
     R 1 , R 2  and R 3  are independently represent hydrogen, halogen, hydrocarbyl (—R), hydroxyl (—OH), hydrocarbyloxy (—O—R), mercapto (—SH), hydrocarbylthio (—S—R), hydrocarbylsulfinyl (—SO—R), hydrocarbylsulfonyl (—SO 2 —R), nitro (—NO 2 ), amino (—NH 2 ), hydrocarbylamino (—NHR), bis(hydrocarbyl)amino (—NR 2 ), hydrocarbylcarbonylamino (—NH—CO—R), cyano (—CN), carbamoyl (—CONH 2 ), hydrocarbylcarbarnoyl (—CONHR), bis(hydrocarbyl)carbamoyl (—CONR 2 ), carboxyl (—CO 2 H), hydrocarbyloxycarbonyl (—CO 2 R), formyl (—CHO), hydrocarbylcarbonyl (—COR), hydrocarbylcarbonyloxy (—OCOR), optionally substituted heteroaryl or optionally substituted heterocyclic; and  
     the hydrocarbyl group R is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl, which may optionally be substituted by one or more substituents, selected from those defined above in relation to R1, R2 and R3]; are of use in the manufacture of a medicament for the treatment including prophylaxis of disease mediated by the activation of GSK-3.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention is enclosed within the pharmaceuticalresearch and industry field. In particular, it is centred on theidentification of previously described or new chemical compounds usefulin the treatment of any pathology related to the phosphorylatingactivity of the enzyme GSK-3 as, for instance, Alzheimer's Disease, AD.

BACKGROUND OF THE INVENTION

[0002] The progressive ageing of the world population brings on theundesired consequence of an increase in the incidence of seniledementia, The most widely spread of this dementia is AD, which affectsnear 50% of the population aged 85 years or more and, as longevityincreases, this rate will also increase unless the strategies to preventor arrest the neurocdegenerative processes become successful.

[0003] There are several biochemical processes affected in AD patients.The treatment of these pathologies would be a correct approach todiminish the damage caused by the disease but, up to now, the only drugscommercialised are some agents that improve cholinergicneurotransmission. Although temporarily, they alleviate the cognoscitiveand memory failures associated to AD, At present, most of the researchis mainly focused on the search of new agents useful in the treatment oftwo other pathologies, senile plaques and neurofibrillary tangles, whichconstitute the major histological lesions observed in AD brains and arealso associated with the cholinergic neurotransmission [“Modulation ofβ-amyloid precursor protein processing and tau phosphorylation byacetylcholine receptors” Hellström-Lindahl, E.; Eur. J. Pharmacology2000, 393, 255-2633].

[0004] The object of this invention is precisely related to thediscovery of new products which are able to interfere the developing ofneurofibrillary tangles. These tangles are formed by paired helicalfilaments whose main component is an intracellular, polar, quitehydrosoluble, microtubule-associated phosphoprotein protein named tauwhich appears abnormally phosphorylated. In normal cells, tau isessential for the integrity and stability of the neuronal cytoskeletonbut its biological activity appears regulated by the degree ofphosphorylation: normal brain tau contains 2-3 moles phosphate/moleprotein while AD abnormally hyperphosphorylated tau contains 5-9 molesphosphate/mole protein [“Brain microtubule associated proteins:Modifications and disease” (Kosic, K. and Avila, J. Eds.) Chap. 7: “Tauphosphatases” Iqbal, K. et al. Harwood Academic Publishers, New York,pp. 95-111 (1997)]. Pathological tau presents a diminished capacity tostabilise microtubules, bringing on the corresponding neuronaldegeneration, and aggregates into the filaments that form the tangles.

[0005] Hyperphosphorylation of tau and progress of AD relation is welldemonstrated. Thus, selective inhibitors of the enzymes (kinases) thatcatalyse the abnormal phosphorylation of tau could become very usefultherapeutic agents in the treatment of AD. In fact, the search for theseinhibitors is an outstanding field of current pharmaceutical research[“Tau protein as a therapeutic target in Alzheimer's disease and otherneurodegenerative diseases” Larner, A. J.; Expert Opinion on TherapeuticPatents 1999, 9, 1359-1370].

[0006] Neither the whole tau hyperphosphorylation process nor all thekinases involved in it are completely known, but it is clear that GSK-3is an in vivo kinase in brain and that it plays a central role in thepathological process. The discovery of non-toxic GSK-3 inhibitors wouldbe very important, both from the scientific and industrial points ofview, because, until now, the lithium cation is the only agent that haveproved to inhibit GSK-3 but in therapeutically unacceptable highconcentrations. A comprehensive review on this subject may be found in“Inhibition of tau phosphorylation: a new therapeutic strategy for thetreatment of Alzheimer's disease and other neurodegenerative disorders”Castro, A.; Martinez, A.; Expert Opinion on Therapeutic Patents 2000,10, 1519-1527. It has also been observed that insulin inactivates GSK-3and that non-dependent insulin diabetes mellitus is related to theactivation of the enzyme, so, there is the possibility that GSK-3inhibitors could became new useful agents in the treatment of that kindof diabetes.

[0007] Research conducted by the present applicants has recently shownthat a new family of aromatic and heteroaromatic ketones exhibit GSK-3inhibitor activity at a micromolar or lower concentration level, thusleading to the completion of the present invention.

DESCRIPTION OF THE INVENTION

[0008] In a first aspect, the present invention provides compounds ofgeneral formula I:

[0009] wherein:

[0010] X represents —CH═CH—, —CH═CR—, —CR═CR—, —CO—, —O—, —NH—, —NR—,—S—, —SO—, —SO₂—, —CH═N—, —CR═N—, —CH═N(O)—, —CR═N(O)— or any other atomor group of atoms capable of forming a 5- or 6-membered heterocyclicring;

[0011] Y¹, Y² and Y³ independently represent hydrogen or halogen;

[0012] R¹, R² and R³ are independently represent hydrogen, halogen,hydrocarbyl (—R), hydroxyl (—OH), hydrocarbyloxy (—O—R), mercapto (—SH),hydrocarbylthio (—S—R), hydrocarbylsulfinyl (—SO—R), hydrocarbylsulfonyl(—SO₂—R), nitro (—NO₂), amino (—NH₂), hydrocarbylamino (—NHR),bis(hydrocarbyl)amino (—NR₂), hydrocarbylcarbonylamino (—NH—CO—R), cyano(—CN), carbamoyl (—CONH₂), hydrocarbylcarbamoyl (—CONHR),bis(hydrocarbyl)carbamoyl (—CONR₂), carboxyl (—CO₂H),hydrocarbyloxycarbonyl (—CO₂R), formyl (—CHO), hydrocarbylcarbonyl(—COR), hydrocarbylcarbonyloxy (—OCOR), optionally substitutedheteroaryl or optionally substituted heterocyclic;

[0013] the hydrocarbyl group R is a straight or branched chainhydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl,aralkenyl and aralkynyl, which may optionally be substituted by one ormore substituents, selected from those defined above in relation to R¹,R² and R³.

[0014] As described below, the compounds of formula (I) are inhibitorsof kinases in general and of GSK-3 in particular, and are thereforeuseful as possible therapeutic agents.

[0015] Therefore, in a second aspect, the invention provides the use ofa compound of formula (I) as a medicament, in particular in themanufacture of a medicament for the treatment including prophylaxis ofdiseases mediated by the activation of GSK-3.

[0016] In a third aspect, the invention provides a method of treating amammal, notably a human, affected by a disease mediated by theactivation of GSK-3, which comprises administering to the affectedindividual a therapeutically effective amount of a compound of formula(I), or a pharmaceutical composition thereof.

[0017] In further aspects, the present invention provides apharmaceutical preparation which contain as active ingredient a compoundor compounds of the invention, as well as a process for the preparationof such a pharmaceutical.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0018] In the compounds of formula (I), the hydrocarbyl group R and thehydrocarbyl component of the other groups is a straight or branchedchain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl,aralkyl, aralkenyl and aralkynyl. These are defined in more detailbelow.

[0019] In the definitions used in the present application, alkyl groupsmay be straight or branched chain groups and preferably have from 1 toabout 12 carbon atoms, more preferably 1 to about 8 carbon atoms, stillmore preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl areparticularly preferred alkyl groups in the compounds of the presentinvention. As used herein, the term alkyl, unless otherwise modified,refers to both cyclic and noncyclic groups, although cyclic groups willcomprise at least three carbon ring members.

[0020] Preferred alkenyl and alkynyl groups in the compounds of thepresent invention have one or more unsaturated linkages and from 2 toabout 12 carbon atoms, more preferably 2 to about 8 carbon atoms, stillmore preferably 2 to about 6 carbon atoms, even more prefereably 2, 3 or4 carbon atoms. The terms alkenyl and alkynyl as used herein refer toboth cyclic and noncyclic groups, although straight or branchednoncyclic groups are generally more preferred.

[0021] The aryl groups in the compounds of the present inventionpreferably have 6 to 10 carbon atoms in a single aromatic carbocyclicring or in two or more fused rings. Phenyl and naphthyl groups,especially the phenyl group, are preferred.

[0022] The aryl groups may optionally be substituted on the aromaticring by one or more substituents. When more than one substituent ispresent, the substituents may be the same or different. The number ofsubstituents on the aryl group is restricted only by the number ofsubstitutable positions and by steric constraints. However, we preferthat the aryl groups have from 1 to 5, more preferably 1 to 3, stillmore preferably 1 or 2, and most preferably only 1 substituent. Thesubstituents may include hydrocarbyl, hydroxyl, hydrocarbyloxy,mercapto, hydrocarbylthio, hydrocarbylsulfinyl, hydrocarbylsulfonyl,nitro, amino, hydrocarbylamino, bis(hydrocarbyl)amino,hydrocarbylcarbonylamino, cyano, carbamoyl, hydrocarbylcarbamoyl,bis(hydrocarbyl)carbamoyl, carboxyl, hydrocarbyloxycarbonyl, formyl,hydrocarbylcarbonyl, hydrocarbylcarbonyloxy, optionally substitutedheteroaryl or optionally substituted heterocyclic which are defined inmore detail elsewhere in this specification.

[0023] Preferred aralkyl groups in the compounds of the presentinvention comprise an alkyl group having from 1 to 6 carbon atoms whichis substituted with an aryl group as defined above to form an aralkylgroup having a total of 7 to 16 carbon atoms. The aryl part of thearalkyl group may optionally be substituted on the aromatic ring by oneor more substituents, the number and type of which is described above inrelation to aryl groups. Examples of preferred aralkyl groups includebenzyl, phenethyl, phenylpropyl, 1-naphthylmethyl and naphthylethyl, ofwhich the benzyl group is most preferred.

[0024] Preferred aralkenyl and aralkynyl groups in the compounds of thepresent invention comprise an alkenyl or alkynyl group (preferablyhaving 2 to 6 carbon atoms) which is substituted with an aryl group (asdefined above) to form an aralkenyl or aralkynyl group having a total of8 to 16 carbon atoms, Examples of preferred aralkyl groups includephenylethenyl (styryl) and phenylethynyl.

[0025] The hydrocarbyl groups in the compounds of the present inventionmay be substituted by a number of different groups, includinghydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio,hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino,hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino,cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl,carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl,hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionallysubstituted heterocyclic, which are defined in more detail elsewhere inthis specification. The number of substituents on the hydrocarbyl groupis restricted only by the number of substitutable positions and bysteric constraints. However, we prefer that the hydrocarbyl groups havefrom 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, andmost preferably only 1 substituent.

[0026] The definitions given above for the various types of hydrocarbylgroups in the compounds of the present invention also apply to thehydrocarbyl part of the other possible groups in these compounds. Theseare defined in more detail below for the preferred case wherein thehydrocarbyl group is an alkyl group.

[0027] Preferred alkoxy groups in the compounds of the present inventioninclude groups having one or more (but preferably only one) oxygenlinkages and from 1 to about 12 carbon atoms, more preferably from 1 toabout 8 carbon atoms, and still more preferably 1 to about 6 carbonatoms, and most preferably 1, 2, 3 or 4 carbon atoms.

[0028] Preferred alkylthio groups in the compounds of the presentinvention have one or more (but preferably only one) thioether linkagesand from 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferably 1 to about 6 carbon atoms.Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

[0029] Preferred alkylsulfinyl groups in the compounds of the presentinvention include those groups having one or more sulfoxide (SO) groupsand from 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

[0030] Preferred alkylsulfonyl groups in the compounds of the presentinvention include those groups having one or more sulfonyl (SO₂) groupsand from 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

[0031] The halogen atoms in the compounds of the present invention arepreferably fluorine, chlorine, bromine or iodine, of which chlorine andbromine are more preferred.

[0032] Preferred alkylcarbonyl (alkanoyl) groups in the compounds of thepresent invention include those groups having one or more carbonyl (CO)groups and from 1 to about 30 carbon atoms, more preferably from 1 toabout 12 carbon atoms, and still more preferably 1 to about 6 carbonatoms (including the carbonyl carbon). Alkanoyl groups having 1, 2, 3 or4 carbon atoms, especially the formyl, acetyl, propionyl, butyryl andisobutyryl groups, are preferred and the acetyl group is especiallypreferred.

[0033] The alkanoyl group may be substituted with one or more (butpreferably only one) substituents, which may preferably be selected fromhalogen, hydroxy, alkoxy and cyano, especially a halogen atom,particularly chlorine or bromine.

[0034] Preferred alkylcarbonyloxy (alkanoyloxy) groups in the compoundsof the present invention include those groups having one or morecarbonyloxy groups and from 1 to about 30 carbon atoms, more preferablyfrom 1 to about 12 carbon atoms, and still more preferably 1 to about 6carbon atoms (including the carbonyl carbon). When the term“alkanoyloxy” is used, it is to be understood that the group is attachedto the rest of the molecule via the oxygen atom. Alkanoyloxy groupshaving 1, 2, 3 or 4 carbon atoms, especially the formyloxy, acetoxy,propionyloxy, butyryloxy and isobutyryloxy groups, are preferred and theformyloxy and acetyloxy groups especially preferred.

[0035] Preferred alkylcarbonylamino (alkanoylamino) groups in thecompounds of the present invention include those-groups having an—NH—CO— linkage (the group being attached to the rest of the moleculevia the nitrogen atom) and from 1 to about 30 carbon atoms, morepreferably from 1 to about 12 carbon atoms, and still more preferably Ito about 6 carbon atoms (including the carbonyl carbon). the group isattached to the rest of the molecule via the nitrogen atom.Alkanoylamino groups having 1, 2, 3 or 4 carbon atoms, especially theformylamino, acetylamino, propionylamino, butyrylamino andisobutyrylamino groups, are preferred and the formylamino andacetylamino groups especially preferred.

[0036] Preferred N-alkylcarbamoyl groups in the compounds of the presentinvention comprise a —CO—NH— linkage (the group being attached to therest of the molecule via the carbonyl carbon) wherein the nitrogen atomis substituted with an alkyl group having from 1 to about 12 carbonatoms, more preferably 1 to about 6 carbon atoms. N-Alkylcarbamoylgroups having 1, 2, 3 or 4 carbon atoms, especially theN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl andN-butylcarbamoyl groups, are particularly preferred.

[0037] Preferred dialkylcarbamoyl groups in the compounds of the presentinvention comprise a —CO—N— linkage (the group being attached to therest of the molecule via the carbonyl carbon) wherein the nitrogen atomis substituted with two alkyl groups, each having from 1 to about 12carbon atoms, more preferably 1 to about 6 carbon atoms. The alkylgroups may be the same or different. N,N-Dialkylcarbamoyl groups whereineach alkyl group has 1, 2, 3 or 4 carbon atoms, especially the N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,N-ethyl-N-propylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyland N-methyl-N-butylcarbamoyl groups, are particularly preferred.

[0038] Preferred monoalkylamino groups in the compounds of the presentinvention have one or more (but preferably only one) NH linkages andfrom 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferably 1 to about 6 carbon atoms.Alkylamino groups having 1, 2, 3 or 4 carbon atoms, especially themethylamino, ethylamino, propylamino and butylamino groups, areparticularly preferred.

[0039] Preferred dialkylamino groups in the compounds of the presentinvention have one or more (but preferably only one) nitrogen atombonded to two alkyl groups, each of which may from 1 to about 12 carbonatoms, more preferably from 1 to about 8 carbon atoms, and still morepreferably 1 to about 6 carbon atoms. The alkyl groups may be the sameor different. Dialkylamino groups wherein each alkyl group has 1, 2, 3or 4 carbon atoms, especially the dimethylamino, diethylamino,N-methylethylamino, N-ethylpropylamino, dipropylamino, dibutylamino andN-methylbutylamino groups, are particularly preferred.

[0040] Preferred alkoxycarbonyl groups in the compounds of the presentinvention include those groups having one or more (but preferably onlyone) oxycarbonyl groups and from 1 to about 30 carbon atoms, morepreferably from 1 to about 12 carbon atoms, and still more preferably 1to about 6 carbon atoms (including the carbonyl carbon). When the term“alkoxycarbonyl” is used, it is to be understood that the group isattached to the rest of the molecule via the carbonyl carbon.Alkoxycarbonyl groups having 1, 2, 3 or 4 carbon atoms, especially themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl arepreferred and the methoxycarbonyl and ethoxycarbonyl groups especiallypreferred.

[0041] Heteroaromatic groups in the compounds of the present inventionpreferably have from 5 to 14 ring atoms in a single aromatic ring or in2 or more fused rings. At least one of the ring atoms (preferably from 1to 4 ring atoms, more preferably 1 to 3 ring atoms, even more preferably1 or 2 ring atoms, and most preferably 1 ring atom) is a heteroatom,which is preferably selected from nitrogen, oxygen and sulfur atoms. Theheteroaromatic group may optionally be fused to another heteroaromaticgroup or to an aryl group, examples of which are defined above. Examplesof preferable heteroaromatic groups include pyridyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,tetrazolyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl,benzimidazolyl, benzofuryl, benzothienyl and benzisoxazolyl.

[0042] The heteroaromatic groups in the compounds of the presentinvention may be substituted by a number of different groups, includinghydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio,hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino,hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino,cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl,carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl,hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionallysubstituted heterocyclic, which are defined in more detail elsewhere inthis specification. The number of substituents on the heteroaromaticgroup is restricted only by the number of substitutable positions and bysteric constraints. However, we prefer that the heteroaromatic groupshave from 1 to 5, more preferably 1 to 3, still more preferably 1 or 2,and most preferably only 1 substituent.

[0043] The heterocyclic groups (other than the heteroaromatic groupsdefined above) in the compounds of the present invention preferablycontain from 3 to 14 ring atoms in a single ring or 2 or more fusedrings. At least one of the ring atoms (preferably from 1 to 4 ringatoms, more preferably 1 to 3 ring atoms, even more preferably 1 or 2ring atoms, and most preferably 1 ring atom) is a heteroatom, which ispreferably selected from nitrogen, oxygen and sulfur atoms. Theheterocyclic group may optionally be fused to a cycloalkyl group, aheterocyclic group, an aryl group or a heteroaromatic groups, examplesof which are defined above. Preferred heterocyclic groups includeazetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, chromanyl andthiochromanyl.

[0044] The heterocyclic groups in the compounds of the present inventionmay be substituted by a number of different groups, includinghydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio,hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino,hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino,cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl,carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl,hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionallysubstituted heterocyclic, which are defined in more detail elsewhere inthis specification. The number of substituents on the heterocyclic groupis restricted only by the number of substitutable positions and bysteric constraints. However, we prefer that the heterocyclic groups havefrom 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, andmost preferably only 1 substituent.

[0045] Preferably X is selected from —CH═CH—, —CH═CR—, —CR═CR—, —CH═N—,—CR═N—, —O—, —NH—, —NR—, and —S— (the group R representing C₁₋₆ alkyl orC₆₋₁₀ aryl).

[0046] More preferably, X is selected from —CH═CH—, —CH═CR—, —CR═CR—,—O— and —S— (the group R representing C₁₋₆ alkyl).

[0047] Most preferably, X is selected from —CH═CH— and —S—.

[0048] Preferably, one or two of Y¹, Y² and Y³ are halogen, and theother two or one are hydrogen.

[0049] More preferably, one of Y¹, Y² and Y³ is halogen, and the othertwo are hydrogen.

[0050] Most preferably, one of Y¹, Y² and Y³ is chlorine or bromine, andthe other two are hydrogen.

[0051] Iodo is also a preferred possibility for one of the Y groups,with the other two being hydrogen.

[0052] Preferably, R¹, R² and R³ are independently selected fromhydrogen, halogen, C₁₋₆ alkyl (which may be optionally substituted withone or more substituents selected from halogen, hydroxy, C₁₋₆ alkoxy andcyano), C₆₋₁₀ aryl, optionally substituted C₇₋₁₆ aralkyl, hydroxy, C₁₋₆alkoxy, C₆₋₁₀ aryloxy, C₇₋₁₆ aralkyloxy, C₁₋₆ alkylthio, C₆₋₁₀ arylthio,C₇₋₁₆ aralkylthio, C₁₋₆ alkylsulfinyl, C₆₋₁₀ arylsulfinyl, C₇₋₁₆aralkylsulfinyl, C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₇₋₁₆aralkylsulfonyl, cyano, carboxyl, C₁₋₆ alkyloxycarbonyl, C₇₋₁₁aryloxycarbonyl, C₈₋₁₆ aralkyloxycarbonyl, heteroaryl and C₁₋₃₀aliphatic acyl (which may be optionally substituted with one or moresubstituents selected from halogen, hydroxy and C₁₋₆ alkoxy and cyano)).

[0053] More preferably, R¹, R² and R³ are independently selected fromhydrogen, halogen, C₁₋₆ alkyl (which may be optionally substituted withone or more substituents selected from halogen, hydroxy and C₁₋₆alkoxy), C₁₋₆ alkoxy, C₆₋₁₀ aryl, heteroaryl, nitro, amino and C₁₋₂₀aliphatic acyl (which may be optionally substituted with one or moresubstituents selected from halogen, hydroxy and C₁₋₆ alkoxy and cyano).

[0054] Still more preferably, R¹, R² and R³ are independently selectedfrom hydrogen, halogen, C₁₋₄ alkyl (which may be optionally substitutedwith one or more halogen atoms), C₁₋₄ alkoxy, C₆₋₁₀ aryl, heteroaryl,nitro, amino and C₂₋₆ aliphatic acyl (which may be optionallysubstituted with one or more halogen atoms), provided that at least oneof R₁, R² and R³ are other than hydrogen.

[0055] Yet more preferably, R¹, R² and R³ are independently selectedfrom hydrogen, chlorine, bromine, methyl, ethyl, methoxy, ethoxy,acetyl, chloroacetyl, phenyl, morpholino, nitro, amino and bromoacetyl,provided that at least one of R¹, R² and R³ is other than hydrogen.

[0056] Even more preferably, R¹, R² and R³ are independently selectedfrom hydrogen, chlorine, bromine, methyl, methoxy, phenyl, morpholino,nitro, amino and chloroacetyl, provided that at least one of R¹, R² andR³ is other than hydrogen.

[0057] As the person skilled in the art will readily appreciate, thepreferred definitions of X, Y¹, Y², Y³, R¹, R², and R³ may be combinedin various ways, and the compounds covered by all such combinations andpermutations of the above preferred definitions are to be considered asbeing part of this invention. More especially, we prefer compoundswherein —X— is —S— or —CH═CH—; is bromo-, dibromo-, chloro-, dichloro-or iodo- acetyl; R¹ is one of the possibilities listed in Table 1 forR¹, R² or R³; R² is one of the possibilities listed in Table 1 for R¹,R² or R³; and R³ is one of the possibilities listed in Table 1 for R¹,R² or R³.

[0058] Preferred compounds of formula (I) are selected from thefollowing Table 1. TABLE 1 I

comp. —X— COCY¹Y²Y³ R¹ R² R³ 1 —S— 3-COCH₂Cl 2-Br 4-Cl 5-Cl 2 —S—2-COCH₂Cl 4-Cl 5-Cl H 3 —S— 2-COCH₂Cl 4-Br H H 4 —S— 3-COCH₂Cl 4-Cl H H5 —S— 3-COCH₂Cl 2-Br 4-Br 5-Br 6 —S— 3-COCH₂Cl 2-Cl 5-Cl H 7 —S—2-COCH₂Cl 5-Cl H H 8 —S— 2-COCH₂Cl 5-Br H H 9 —S— 2-COCH₂Cl 4-COCH₂Cl HH 10 —S— 2-COCH₂Cl H H H 11 —S— 2-COCH₂Cl 4-COCH₂Cl 5-CH₃ H 12 —S—2-COCH₂Cl 5-CH₃ H H 13 —S— 3-COCH₂Cl 2-CH₃ 5-CH₃ H 14 —S— 2-COCH₂Cl 4-Br5-Br H 15 —S— 2-COCH₂Cl 3-Br 4-Br H 16 —S— 2-COCH₂Cl 3-CH₃ 4-COCH₂Cl H17 —S— 2-COCH₂Cl 4-CH₃ H H 18 —S— 2-COCH₂Cl 3-CH₃ H H 19 —S— 2-COCH₂Cl5-COCH₃ H H 20 —S— 2-COCH₂Cl 4-COCH₃ H H 21 —S— 2-COCH₂Br 3-Br 4-Br H 22—S— 2-COCH₂Br 4-Br 5-Br H 23 —S— 2-COCH₂Br 5-Br H H 24 —CH═CH— COCH₂Cl4-Cl H H 25 —CH═CH— COCH₂Cl H H H 26 —CH═CH— COCH₂Br 2-Br 4-Br 6-Br 27—CH═CH— COCH₂Br 3-Br 4-Br H 28 —CH═CH— COCH₂Br 4-Br H H 29 —CH═CH—COCH₂Br 4-Cl H H 30 —CH═CH— COCH₂Br H H H 31 —CH═CH— COCH₂Br 4-CH₃ H H32 —CH═CH— COCH₂Br 4-OCH₃ H H 33 —CH═CH— COCH₂Br 4-Ph H H 34 —CH═CH—COCHBrCl 4-Cl H H 35 —CH═CH— OCCHBrCl H H H 36 —CH═CH— COCHBr₂ H H H 37—CH═CH— COCHBr₂ 4-Br H H 38 —CH═CH— COCH₂Br 4-CN H H 39 —CH═CH— COCHBr₂4-CN H H 40 —CH═CH— COCH₂Br 4-CF₃ H H 41 —CH═CH— COCHBr₂ 4-CF₃ H H 42—CH═CH— COCH₂Br 4-Morpholine H H 43 —CH═CH— COCH₂Br 3-CN H H 44 —CH═CH—COCHBr₂ 3-CN H H 45 —CH═CH— COCHBr₂ 4-I H H 46 —CH═CH— COCH₂Br 4-NO₂ H H47 —CH═CH— COCH₂Br 3-Br 4-NH₂ 5-Br 48 —CH═CH— COCH₂I 4-Br H H

[0059] In further aspects, the present invention provides apharmaceutical preparation, which contains as active ingredient acompound or compounds of the invention, as well as a process for itspreparation.

[0060] Examples of pharmaceutical compositions include any solid(tablets, pills, capsules, granules, etc.) or liquid (solutions,suspensions or emulsions) with suitable composition or oral, topical orparenteral administration, and they may contain the pure compound or incombination with any carrier or other pharmacologically activecompounds. These compositions may need to be sterile when administeredparenterally.

[0061] Synthesis of the Compounds of the Invention

[0062] Most of the compounds whose biological activity is the object ofthe present invention can be synthesised following a general procedurepreviously described [Conde, S.; Corral, C.; Madro{overscore (n)}ero,R.; Sánchez Alvarez-Insúa, A.; Fernández-Tomé M. P.; del Río. J.; J.Med. Chem. 1977, 20, 970-974]. Following this synthetic method, anaromatic or heteroaromatic compound of formula II reacts with a mixtureof a substituted acetyl halide of formula III, e. g. chloroacetylchloride, bromoacetyl bromide, etc, and a Lewis acids, such as TiCl₄,SnCl₄, AlCl₃, etc, in an aprotic anhydrous organic solvent, for example,CS₂, CCl₄, etc. This process is represented in Scheme 1, where Y′represents a halogen atom (F, Cl, Br or I).

[0063] Another group of compounds can be synthesised by the generalsynthetic procedure of halogenation [described, for example, in: Seeger,D. E.; Lahti, P. M.; Rossi, A. R.; Benson, J. A.; J. Am. Chem. Soc.1986, 108, 1251-1265] represented in Scheme 2. Following this procedure,an aromatic or heteroaromatic ketone IV is treated with the desiredhalogen in the medium of a polar organic solvent, such as acetic acid,dioxane, etc, to obtain the α-halomethyl ketone V, which falls withinthe scope of compounds of formula I but has a single halogen atom Y.

[0064] Activity of the Compounds of the Invention

[0065] In the following examples, the selective enzyme GSK-3 inhibitionby the compounds of the invention is demonstrated. As described above,it has been established that the enzyme GSK-3 plays a crucial role inthe ethiopathogenia of AD as responsible of the hyperphosphorylation ofthe protein tau observed in this pathology. Because of the biologicalactivity of these products as GSK-3 inhibitors, they can be consideredas important prototypes or lead compounds of a new family of compoundsthat can prevent the formation of neurofibrillary tangles and reversethose already formed.

[0066] The compounds of the invention are capable of inhibiting theenzyme GSK-3. The compounds of the invention are therefore useful astherapeutical agents in the treatment of neurodegenerative diseases,such as AD or any other associated to the pathology of protein tau, orto the activation of GSK-3, such as non-insulin dependent diabetesmellitus.

[0067] In addition, due to their ability to inhibit the cellular cycle,the compounds of the invention are also useful in the treatment ofhyperproliferative diseases, for example, displasias and metaplasias ofdifferent tissues, psoriasis, arteriosclerosis and cancer. Theirapplication in the treatment of these pathologies forms also part of thepresent invention.

[0068] WO 9640982 provides compositions for therapy of neurodegenerativedisease comprising an efficacious amount of a selective PLA₂ inhibitor.p-Bromophenacyl bromide is given as an example of such a selective PLA₂inhibitor. The present invention disclaims this use of p-bromophenacylbromide. In preferred compounds of this invention, a phenacyl bromide isnot subsituted with one substituent which is p-bromo, or ap-bromoacetophenone compound does not have one subsituent which isα-bromo, or the compound is not a selective PLA₂ inhibitor.

EXAMPLES

[0069] Synthesis of Some of the Compounds of the Invention

Examples 1 and 2

[0070] 1-(2-Bromo-4,5-dichloro-thiophen-3-yl)-2-chloro-ethanone (1) and2-Chloro-1-(4,5-dichloro-thiophen-2-yl)-ethanone (2) (GeneralProcedure).

[0071] Chloroacetyl chloride (4.60 ml, 0.058 mol) was added to a stirredsuspension of aluminium trichloride (7.70 g, 0.058 mol) in carbondisulphide (50 ml) placed in a 250 ml round-bottom flask equipped with areflux condenser, an addition funnel and a magnetic stirring bar. Themixture was stirred at room temperature overnight and then refluxed for1 h. Afterwards, the reaction was ice-cooled an treated with 1N aqueousHCl (50 ml). The organic layer was separated, washed with water, driedover magnesium sulphate and the solvent evaporated. The residue yieldedtwo compounds by chromatography column (hexane:ethyl acetate 10:1): thecompound 1 (9.72 g, 63%) [m.p.:85-86° C. (heptane), ¹H—NMR (CDCl₃):δ=4.68 (s, CH₂Cl)] and a second compound (2) identified as2-chloroacetyl-4,5-dichlorothiophene (2.53 g, 22%), previously described[del Agua et al J. Heterocyclic Chem. 1981, 18,1345-1347].

Example 3

[0072] 1-(4-Bromo-thiophen-2-yl)-2-chloro-ethanone

[0073] This compound was previously described by Conde et al [J. Med.Chem. 1977, 20, 970-974].

Example 4

[0074] 2-Chloro-1-(4-chloro-thiophen-3-yl)-ethanone

[0075] This compound was previously described by Conde et al [J. Med.Chem. 1977, 20, 970-974].

Example 5

[0076] 2-Chloro-1-(2 4,5-tribromo-thiophen-3-yl) -ethanone.

[0077] This compound was previously described by del Agua et al [J.Heterocyclic Chem. 1981, 18, 1345-1347].

Example 6

[0078] 2-Chloro-1-(2,5-dichloro-thiophen-3-yl)-ethanone.

[0079] General procedure described for compounds 1 and 2 starting from2,5-dichlorothiophene and chloroacetyl chloride. Purified by columnchromatography column (hexane:ethyl acetate 12:1), yield 91%, m.p.:43-44° C. (ethanol), ¹H-NMR (CDCl₃): δ7.1 (s, 1H, CH-Aromat), 4.6 (s,2H, CH₂); ¹³C-NMR (CDCl₃) : 186.6 (CO), 136.9 (C—Cl), 136.0 (C—CO),130.2 (C—Cl), 129.4 (CH—Ar), 50.6 (CH₂); M/z (EI): 234, 232, 230, 228(M⁺, 1, 6, 16, 16%), 183, 181, 179 (M-CH₂Cl, 18, 79, 100%), 155, 153,151 (M-COCH₂Cl, 3, 13, 19%), 118, 116 (M-COCH₂Cl₂, 5, 13%); HPLC: DeltaPak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 99%, r.t.=6.16 min,acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50.

Example 7

[0080] 2-Chloro-1-(5-cbloro-thioiphen-2-yl)-ethanone

[0081] This compound was previously described by Emerson et al. [J. Org.Chem. 1948, 13, 729-730].

Example 8

[0082] 1 -(5-Bromo-thiophen-2-yl)-2-chloro-ethanone.

[0083] This compound was previously described by del Agua et al [J.Heterocyclic Chem. 1981, 18, 1345-1347].

Examples 9 and 10

[0084] 2-Chloro-1-[4-(2-chloro-acetyl)-thiophen-2-yl]-ethanone (9) and2-Chloro-1-thiophen-2-yl-ethanone (10)

[0085] General procedure described for compounds 1 and 2 starting fromthiophene and chloroacetyl chloride. Two products were isolated bycolumn chromatography column (hexane:ethyl acetate 4:1). Compound 9:yield 68%, m.p.: 154-155° C. (water/methanol), ¹H-NMR (CDCl₃): δ8.4 (s,1H, H₅), 8.2 (s, 1H, H₃), 4.6 (s, 2H, CH₂), 4.5 (s, 2H, CH₂); ¹³C-NMR(CDCl₃): δ189.0 (CO), 188.2 (CO), 145.9 (C—CO), 144.3 (CH), 143.3(C—CO), 135.9(CH), 49.7 (CH₂), 49.1 (CH₂); M/z (EI): 240, 238, 236 (M⁺,1, 2, 8%), 189, 187 (M-CH₂Cl, 39, 100%); HPLC: Delta Pak Column C18, 5μm, 300 A, (150×3.9 mm), Purity 96%, r.t.=3.21 min, acetonitrile/H₂O(0.05% H₃PO₄+0.04% Et₃N)]50/50. Compound 10 (13%) was previouslydescribed by Nakayama, J. et al [Heterocycles. 1987, 26, 10, 2599-2602].

Examples 11 and 12

[0086] 2-Chloro-1-]4-(2-chloro-acetyl)-5-methyl-thiophen-2-yl]-ethanone(11) and 2-Chloro-1-(5-methyl-thiophen-2-yl)-ethanone (12)

[0087] General procedure described for compounds 1 and 2 starting from2-methylthiophene and chloroacetyl chloride. Two products were isolatedby column chromatography column (hexane:ethyl acetate 6:1). Compound 11:yield 73%, mrp.: 110-111° C. (hexane), ¹H—NMR (CDCl₃): δ8.0 (s, 1H, Ar),4.54 (s, 2H, CH₂), 4.52 (s, 2H, CH₂), 2.8 (s, 3H, CH₃); ¹³C-NMR (CDCl₃):δ190.3 (CO), 187.7 (CO), 164.6 (C—CH₃), 140.3 (C—CO), 137.4 (C—CO),137.1 (CH), 51.2 (CH₂), 48.9 (CH₂), 21.1 (CH₃); M/z (EI): 254, 252, 250(M⁺, 2, 11, 15%), 203, 201 (M-CH₂Cl, 52, 100%); HPLC: Delta Pak ColumnC18, 5 μm, 300 A, (150×3.9 mnm), Purity 94%, r.t.=3.89 min,acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50. Compound 12 (8%), waspreviously described by Belenkii et al [J. Org. Chem. 1970, 6,2531-2534].

Example 13

[0088] 2-Chloro-1-(2,5 dimethyl-thiophen-3-yl) -ethanone.

[0089] This compound was previously described by Belenkii et al [J. Org.Chem. 1970, 6, 2531-2534].

Example 14

[0090] 2-Chloro-1-(4,5-dibromo-thiophen-2-yl)-ethanone.

[0091] This compound was previously described by del Agua et al [J.Heterocyclic Chem. 1981, 18, 1345-1347].

Example 15

[0092] 2-Chloro-1-(3,4-dibromo- thiophen-2-yl)-ethanone.

[0093] General procedure described for compounds 1 and 2 starting from3,4-dibromothiophene and chloroacetyl chloride. The product was isolatedby column chromatography column (hexane:ethyl acetate 8:1). Yield 97%,m.p.: 86-8 ° C., ¹H-NMR (CDCl₃): δ7.7 (s, 1H, Ar), 4.8 (s, 2H, CH₂);¹³C-NMR (CDCl₃): δ185.4 (CO), 140.0 (C—CO), 133.7 (CH), 120.8 (C—Br),119.6 (C—Br), 50.1 (CH₂); M/z (EI): 322, 320, 318, 316 (M⁺, 3, 11, 15,7%), 271, 269, 267 (M-CH₂Cl, 56, 100, 56%); HPLC: Delta Pak Column C18,5 μm, 300 A, (150×3.9 mm), Purity 94%, r.t.=6.06 min, acetonitrile/H₂O(0.05% H₃PO₄+0.04% Et₃N) 50/50.

Examples 16, 17 and 18

[0094] 2-Chloro-1-[5-(2-chloro-acetyl)-4-methyl-thiophen-3-yl]-ethanone(16), 2-Chloro-1-(4-methyl-thiophen-2-yl)-ethanone (17) and2-chloro-1-(3-methyl-thiophen-2-yl)-ethanone (18)

[0095] General procedure described for compounds 1 and 2 starting from3-methylthiophene and chloroacetyl chloride. Three products wereisolated by column chromatography column (hexane:ethyl acetate 3:1).Compound 16: yield 69%, m.p.: 155-156° C., ¹H-NMR (CDCl₃): δ8.2 (s, 1H,Ar), 4.54 (s, 2H, CH₂), 4.52 (s, 2H, CH₂), 2.8 (s , 3H, CH₃); ¹³C-NMR(CDCl₃): δ187.2 (CO), 185.1 (CO), 148.2 (C—CO), 139.1 (C—CO), 137.9(CH), 48.1 (CH₂), 47.3 (CH₂), 16.0 (CH₃); M/z (EI): 254, 252, 250 (M⁺,1, 6, 9%), 203, 201 (M-CH₂Cl, 47, 100%); HPLC: Column μ Bondapack C18, 5μm, 300 A, (300×3.9 mm), Purity 99%, r.t.=4.73 min, acetonitrile/H₂O(0.05% H₃PO₄+0.04% Et₃N) 50/50. Compound 17: yield 8%, m.p.; 76-77° C.,¹H-NMR (CDCl₃): δ7.6 (s, 1H, Ar), 7.1 (s, 1H, Ar), 4.55 (s, 2H, CH₂),2.3 (s , 3H, CH₃); ¹³C-NMR (CDCl₃): δ188.1 (CO), 144.2 (C—CO), 143.2(C—CH₃), 138.9 (CH), 134.9 (CH), 49.4 (CH₂), 19.5 (CH₃); M/z (EI): 176,174 (M⁺, 9, 23%), 125 (M-CH₂Cl, 100%); HPLC: Column μ Bondapack C18, 5μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=4.56 min, ConditionsAcetonitrile/H₂O [(0.05% H₃PO₄+0.04% Et₃N)] 50/50. Compound 18 yield 5%,yellow oil, ¹H-NMR (CDCl₃): δ7.44 (d, J=4.9 Hz, 1H, Ar), 7.0 (d, J=4.9Hz, 1H, Ar), 4.55 (s, 2H, CH₂), 2.3 (s ,3H, CH₃); ¹³C-NMR (CDCl₃):δ188.2 (CO), 151.3 (C—CH₃), 136.8 (CH), 136.2 (C—CO), 135.0 (CH), 51.5(CH₂), 20.9 (CH₃); M/z (EI): 176, 174 (M⁺, 6, 16%), 125 (M-CH₂Cl, 100%);HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 99%,r.t.=3.65 min, acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50.

Example 19

[0096] 1-(5-Acetyl-thiophen-2-yl)-2-chloro-ethanone.

[0097] General procedure described for compounds 1 and 2 starting from2-acetylthiophene and chloroacetyl chloride. Purified by columnchromatography column (hexane:ethyl acetate 3:1), yield 25%, m.p.:94-95° C., ¹H-NMR (CDCl₃): δ8.3 (d, J=4.2 Hz, 1H, Ar), 8.1 (d, J=4.2 Hz,1H, Ar), 4.55 (s, 2H, CH₂), 2.6 (s, 3H, CH₃); ¹³C-NMR (CDCl₃). δ193.0(CO), 187.8 (CO), 148.3 (C—CO), 142.0 (CH), 141.7 (C—CO), 133.7 (CH),48.3 (CH₂), 29.2 (CH₃); M/z (EI): 204, 202 (M ⁺, 4, 10%), 153 (M-CH₂Cl,100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity98%, r.t.=3.50 min, acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50.

Example 20

[0098] 1-(4-Acetyl-thiophen-2-yl)-2-chloro-ethanone.

[0099] General procedure described for compounds 1 and 2 starting from3-acetylthiophene and chloroacetyl chloride. Purified by columnchromatography column (hexane:ethyl acetate 2:1), yield 41% m.p.:118-119° C., ¹H-NMR (CDCl₃): δ8.3 (s, 1H, Ar), 8.1 (s, 1H, Ar), 4.60 (s,2H, CH₂), 2.56 (s, 3H, CH₃); ¹³C-NMR (CDCl₃): δ191.6 (CO), 184.5 (CO),143.3 (C—CO), 141.7 (C—CO), 139.7 (CH), 132.0 (CH), 45.4 (CH₂), 27.4(CH₃); M/z (EI): 204, 202 (M⁺, 6, 17%), 153 (M-CH₂Cl, 100%); HPLC: DeltaPak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 94%, r.t.=2.70 min,acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50.

Example 21

[0100] 2-Bromo-1- (3,4-dibromo-thiophen-2-yl)-ethanone.

[0101] This compound was previously described by Bagli et al [Can. J.Chem. 1975, 53, 2598].

Example 22

[0102] 2-Bromo-1-(4,5-dibromo-thiophen-2-yl)-ethanone.

[0103] This compound was previously described by Bagli et al [Can. J.Chem. 1975) 53, 2598].

Example 23

[0104] 2-Bromo-1-(5-bromo-thiophen-2-yl)-ethanone.

[0105] This compound was previously described by Raeymaekers et al. [J.Med. Chem. 1966, 9, 545-551].

Example 24

[0106] 2-Chloro-1-(4-chloro-phenyl)-ethanone.

[0107] This compound was previously described by Rao et al. [Synth.Commun. 2000, 30, 15, 2763-2768].

Example 25

[0108] 2-Chloro-1-phenyl-ethanone.

[0109] This compound was previously described by Rao et al. [Synth.Commun. 2000, 30, 15, 2763-2768].

Example 26

[0110] 2-Bromo-1-(2,4,6-tribromo-phenyl)-ethanone.

[0111] General procedure described for compounds 1 and 2 starting from1,3,5-tribromobenzene and bromoacetyl bromide. Purified by columnchromatography column (hexane:ethyl acetate 6:1), yield 45% m.p.: 86-87°C., ¹H-NMR (CDCl₃): δ7.7 (s, 2H, Ar), 4.44 (s, 2H, CH₂); ¹³C-NMR(CDCl₃): δ193.4 (CO), 139.4 (C—CO), 134.5 (CH), 124.7 (C—Br), 119.4(C—Br), 34.6 (CH₂); M/z (EI): 440, 438, 436, 434, 432 (M⁺, 1, 3, 5, 3,1%), 345, 343, 341, 339 (M-CH₂Br, 35, 96, 100, 41%); HPLC: Column μBondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=3.40 min,acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50.

Example 27

[0112] 2-Bromo-1-(3,4-dibromo-phenyl)-ethanone.

[0113] General procedure described for compounds 1 and 2 starting from1,2-dibromobenzene and bromoacetyl bromide. Purified by columnchromatography column (hexane:ethyl acetate 6:1), yield 13% m.p. 60-61°C., ¹H-NMR (CDCl₃): δ8.2 (s, 1H, Ar), 7.8 (d, 2H, Ar), 4.4 (s, 2H, CH₂);¹³C-NMR (CDCl₃): δ189.7 (CO), 134.6 (CH), 134.4 (CH), 134.3 (C—CO),132.0 (C—Br), 128.8(CH), 126.2 (C—Br), 30.4 (CH₂); M/z (EI): 360, 358,356, 354 (M⁺, 5, 14, 14, 5%), 265, 263, 261 (M-CH₂Br, 62, 100, 65%);HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%,r.t.=8.73 min, acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N) 50/50.

Example 28

[0114] 2-Bromo-1-(4-bromo-phenyl)-ethanone.

[0115] This compound was previously described by Huff et al[Heterocycles. 1997, 45, 7, 1363-1384].

Example 29

[0116] 2-Bromo-1-(4-chloro-phenyl)-ethanone.

[0117] This compound was previously described by Collet et al [Bull.Soc. Chim. Fr.1899, 21, 67].

Example 30

[0118] 2-Bromo-1-phenyl-ethanone.

[0119] This compound was previously described by Collet et al [Bull.Soc. Chim. Fr.1897, 76].

Example 31

[0120] 2-Bromo-1-p-tolyl-ethanone.

[0121] This compound was previously described by Huff et al[Heterocycles. 1997, 45, 7, 1363-1384].

Example 32

[0122] 2-Bromo-1-(4-methoxy-phenyl)-ethanone.

[0123] This compound was previously described by Kunckell et al [Chem.Ber.1898, 31, 173]

Example 33

[0124] 1-Biphenyl-4-yl-2-bromo-ethanone.

[0125] This compound was previously described by Barfknecht et al [J.Med. Chem, 1975, 18, 1161-1164].

Example 34

[0126] 2-Bromo-2-chloro-1-(4-chloro-phenyl)-ethanone.

[0127] This compound was previously described by Otto et al [Rocz.Chem.1973, 47, 967-969].

Example 35

[0128] 2-Bromo-2-chloro-1-phenyl-ethanone.

[0129] This compound was previously described by Barluenga et al. [J.Chem. Soc. Perkin Trans. 1.1991, 2, 297-300].

Example 36

[0130] 2,2-Dibromo-1-phenyl-ethanone.

[0131] This compound was previously described by Magen et al.[Tetrahedron. Lett, 1984, 25, 31, 3369-3372].

Example 37

[0132] 2,2-Dibromo-1-(4-bromo-phenyl)-ethanone.

[0133] This compound was previously described by Klingenberg et al.[Org. Synth. Coll. Vol, IV 1963, 110].

Example 38

[0134] 4-(2-Bromoacetyl)-benzonitrile.

[0135] This compound was previously described by Ogata, M et al. [J.Med. Chem, 1987, 30, 8, 1497-1502].

Example 39

[0136] 4-(2,2-Dibromo-acetyl)-benzonitrile.

[0137] This compound was previously described by Izawa et al. [Bull.Chem. Soc. Jpn, 1983, 56, 5, 1490-1496].

Example 40

[0138] 2-Bromo-1-(4-trifluoromethyl-phenyl)-ethanone.

[0139] This compound was previously described by Schroeder et al. [J.Med. Chem, 2001, 44, 20, 3231-3243].

Example 41 2,2-Dibromo-1-(4-trifluoromethyl-phenyl)-ethanone.

[0140] This compound was synthesised by the general procedurerepresented in Scheme 2, a stirred solution of1-(4-trifluoromethyl-phenyl)-ethanone (1 g, 5.3 mmol) ) and acetic acid(50 ml) was refluxed 1 h, then bromine (0.35 ml, 6.9 mmol) was addeddropwise and the mixture refluxed 3 h. After cooling at roomtemperature, water (50 ml) was added and the mixture extracted withCH₂Cl₂ (50 ml), the organic layer was washed with water (50 ml), asolution of NaHCO₃ saturated (50 ml) and finally with NaCl solution (50ml), the organic layer was dried over sodium sulphate and the solventevaporated under reduced pressure. The resulting residue was purified bycolumn chromatography, using a mixture of ethyl acetate:hexane (1:8) aseluent giving two compounds, the titled compound 41 as a yellow solid(45%) m.p.: 40-41° C., ¹H-NMR (CDCl₃): δ8.2 (d, J=8.3 Hz, 2H, Ar), 7.8(d, J=8.3 Hz, 2H, Ar), 6.6 (s, 1H, CH); ¹³C-NMR (CDCl₃): δ184.1 (CO),134.7 (q, J=272.9 Hz, C—CF₃), 132.7 (C—CO), 129.2 (CH), 124.8 (CH),119.5 (q, J=33.09, CF₃), 38.2 (CH); M/z (EI): 348, 346, 344 (M⁺, 1, 6,1%), 173 (M-CHBr₂, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A,(300×3.9 mm), Purity 97%, r.t.=9.96 min, acetonitrile/H₂O (0.05%H₃PO₄+0.04% Et₃N) 50/50. The second compound was identified as2-bromo-1-(4-trifluoromethyl-phenyl)-ethanone (0,6%), described as theexample 40.

Example 42

[0141] 2-Bromo-1-(4-morpholin-4-yl-phenyl)-ethanone.

[0142] This compound was previously described by Diwu et al.[Tetrahedron. Lett, 1998, 39, 28, 4987-4990].

Example 43

[0143] 3-(2-Bromo-acetyl)-benzonitrile.

[0144] This compound was previously described by Tanaka et al. [J. Med.Chem, 1998, 41, 13, 2390-2410].

Example 44

[0145] 3-(2,2-Dibromo-acetyl)-benzonitrile.

[0146] This compound was previously described by Watson et al. [Bioorg.Med. Chem, 1998, 6, 6, 721-734].

Example 45

[0147] 2,2 -Dibromo-1- (4-iodo-phenyl)-ethanone.

[0148] Procedure described in example 41 starting from4-iodoacetophenone. The resulting residue was purified by columnchromatography, using a mixture of hexane:ethyl acetate (6:1) as eluent.Yield 48%, colorless solid m.p.: 77-78° C., ¹H-NMR (CDCl₃): δ7.8 (d,J=4.2 Hz, 2H, Ar), 7.7 (d, J=4.2 Hz, 2H, Ar), 6.3 (s, 1H, CH); ¹³C-NMR(CDCl₃): δ185.8 (CO), 138.6 (CH), 131.3 (CH), 130.4 (C—CO), 103.4 (C—I),39.6 (CH); M/z (EI): 406, 404, 402 (M⁺, 9, 17, 9%), 231, (M-CHBr₂,100%); HPLC: Column Symmetry C18, 5 μm, 300 A, (150×3.9 mm), Purity 94%,r.t.=4.51 min, Conditions Acetonitrile/H₂O (0.05% H₃PO₄+0.04% Et₃N)50/50.

Example 46

[0149] 2-Bromo-1-(4-nitro-phenyl)-ethanone.

[0150] This compound was previously described by Wan et al [J. Org.Chem, 1989, 54, 18, 4473-4474].

Example 47 1-(4-Amino-3,5-dibromo-phenyl)-2-bromo-ethanone.

[0151] Procedure described in example 41 starting fromp-aminoacetophenone and using chloroform as solvent. The final residuewas purified by column chromatography, using a mixture of hexane:ethylacetate (2:1) as eluent. Yield 58% m.p.: 146-147° C. (ethanol), ¹H-NMR(CDCl₃): δ8.0 (s, 2H, Ar), 5.1 (s, 2H, NH₂), 4.2 (s, 2H, CH₂); ¹³C-NMR(CDCl₃): δ187.5 (CO), 147.3 (C—NH₂), 132.7 (CH), 123.3 (C‘CO), 106.2(C—Br), 38.3 (CH₂); M/z (EI): 375, 373, 371, 369 (M⁺, 10, 31, 31, 10%),280, 278, 276 (M-CH₂Br, 64, 100, 67%); HPLC: Column Symmetry C18, 5 μm,300 A, (150×3.9 mm), Purity 96%, r.t.=9.98 min, acetonitrile/H₂O (0.05%H₃PO₄+0.04% Et₃N) 50/50.

Example 48

[0152] 2-Iodo-1-(4-bromo-phenyl)-ethanone.

[0153] This compound was previously described by Shaw et al. [J. Amer.Chem. Soc, 1959, 81, 2532-2537].

EXAMPLES

[0154] Biological Activity as Enzymatic Inhibitors of the Compounds ofthe Invention

[0155] 1. Inhibition of GSK-3.

[0156] The GSK-3 inhibitory activity of the compound mentioned in thisinvention was measured by using a previously described method [Woodget,J. R.; Anal. Biochem. 1989, 180, 237-241]. This method consists of theincubation of commercially available GSK-3 with a phosphate source and aGSK-3 substrate in the presence and absence of the correspondingcompound to be tested, and the measurement of the GSK-3 activity in bothmixtures.

[0157] In particular, the enzyme was incubated at 37° C. for a 20minutes period in buffer [tris pH=7.5 (50 mM), EDTA (1 mM), EGTA (1 mM),DTT (1 mM) and MgCl₂ (10 mM)] supplemented by the synthetic peptide GS 1(15 μM final concentration) as substrate, ATP (15 μM), [γ-³²P]ATP (0.2μC_(i)) and different concentrations of the product to be tested. Afterthat, aliquots of the reaction mixtures are added on phosphocellulosep81 papers. These papers are washed three times with phosphoric acid 1%and the radioactivity incorporated to the GS 1 peptide is measured in aliquid scintillation counter.

[0158] Table 2 shows the data of GSK-3 inhibition, which is the objectof this invention, of some representative compounds. The examplespresented are explanatory and must be regarded as non-limitative inrespect of the scope of protection. The numbers given with the differentsubstituents represents the position of the substituent in thecorresponding ring, in accordance with the IUPAC nomenclature rules. TheGSK-3 inhibition data given as the inhibitory concentration 50, IC₅₀,defined as the concentration of the compound that inhibits the enzyme at50%. TABLE 2 comp. —X— COCY¹Y²Y³ R¹ R² R³ IC_(50 (μM)) 1 —S— 3-COCH₂Cl2-Br 4-Cl 5-Cl 2 2 —S— 2-COCH₂Cl 4-Cl 5-Cl H 2.5 3 —S— 2-COCH₂Cl 4-Br HH 3 4 —S— 3-COCH₂Cl 4-Cl H H 25 5 —S— 3-COCH₂Cl 2-Br 4-Br 5-Br 1 6 —S—3-COCH₂Cl 2-Cl 5-Cl H 5 7 —S— 2-COCH₂Cl 5-Cl H H 10 8 —S— 2-COCH₂Cl 5-BrH H 10 9 —S— 2-COCH₂Cl 4-COCH₂Cl H H 1.5 10 —S— 2-COCH₂Cl H H H 50 11—S— 2-COCH₂Cl 4-COCH₂Cl 5-CH₃ H 5 12 —S— 2-COCH₂Cl 5-CH₃ H H 100 13 —S—3-COCH₂Cl 2-CH₃ 5-CH₃ H 100 14 —S— 2-COCH₂Cl 4-Br 5-Br H 1 15 —S—2-COCH₂Cl 3-Br 4-Br H 0.5 16 —S— 2-COCH₂Cl 3-CH₃ 4-COCH₂Cl H 2.5 17 —S—2-COCH₂Cl 4-CH₃ H H 100 18 —S— 2-COCH₂Cl 3-CH₃ H H 75 19 —S— 2-COCH₂Cl5-COCH₃ H H 50 20 —S— 2-COCH₂Cl 4-COCH₃ H H 8 21 —S— 2-COCH₂Br 3-Br 4-BrH 1 22 —S— 2-COCH₂Br 4-Br 5-Br H 1 23 —S— 2-COCH₂Br 5-Br H H 1 24—CH═CH— COCH₂Cl 4-Cl H H 2.5 25 —CH═CH— COCH₂Cl H H H 50 26 —CH═CH—COCH₂Br 2-Br 4-Br 6-Br 25 27 —CH═CH— COCH₂Cl 3-Br 4-Br H 0.75 28 —CH═CH—COCH₂Cl 4-Br H H 0.5 29 —CH═CH— COCH₂Cl 4-Cl H H 1 30 —CH═CH— COCH₂Cl HH H 5 31 —CH═CH— COCH₂Cl 4-CH₃ H H 2.5 32 —CH═CH— COCH₂Cl 4-OCH₃ H H 133 —CH═CH— COCH₂Cl 4-Ph H H 2.5 34 —CH═CH— COCHBrCl 4-Cl H H 7.5 35—CH═CH— COCHBrCl H H H 7.5 36 —CH═CH— COCHBr₂ H H H 2.5 37 —CH═CH—COCHBr₂ 4-Br H H 0.75 38 —CH═CH— COCHBr₂ 4-CN H H 1.5 39 —CH═CH— COCHBr₂4-CN H H 1.5 40 —CH═CH— COCHBr₂ 4-CF₃ H H 5 41 —CH═CH— COCHBr₂ 4-CF₃ H H5 42 —CH═CH— COCHBr₂ 4-Morpholine H H 6 43 —CH═CH— COCHBr₂ 3-CN H H 1 44—CH═CH— COCHBr₂ 3-CN H H 1 45 —CH═CH— COCHBr₂ 4-I H H 2 46 —CH═CH—COCHBr₂ 4-N0₂ H H 2 47 —CH═CH— COCHBr₂ 3-Br 4-NH₂ 5-Br 3 48 —CH═CH—COCH₂I 4-Br H H 3

[0159] 2. In vitro Effects of Some Compounds on Tau Phosphorilation inCultured Neurones.

[0160] Primary cultured cerebellar neurones were obtained from 7-daysold rat following the procedure described by Levy et al. [Brain Res1984, 290, 77-86]. Experiments were performed at 40-48 hours in vitro.Each compound was added at increasing concentrations following the rangedescribed in Table 3.

[0161] Cells were harvested after 16 hours of treatment and homogenisedin a buffer containing 20 mM Hepes, pH 7.4; 100 mM NaCl; 100 mMNa F; 1mM sodium ortho-vanadate; 5 mM EDTA; and protease inhibitors Complete™.

[0162] Tau- 1 antibody was used to monitor the tau phosphorylationchanges because it is sensitive to dephosphorylation. In additionantibody 7.51 was used to detect the total amount of tau in our culturedneurones. The detection was realised in Western blots and the dataquantified using an imaging densitometer (GS-710 model, BioRad)

[0163] Table 3 shows the data of Tau phosphorylation inhibition inneurones measured by Tau- 1 immunoreactivity obtained from tworepresentative compounds of this invention. The examples presented arefor the purposes of explanation and are non-limitative of the scope ofprotection. The numbers given with the different substituents representsthe position of the substituent in the corresponding ring, in accordancewith the IUPAC nomenclature rules.

[0164] The IC₅₀, in this case, is defined as the concentration of thecompound that produce the inhibition of tau 1-immunoreactivity in thisspecific epitope at a 50% TABLE 3 —X— CO—CY¹Y²Y³ R¹ R² R³ IC₅₀(μM) —S—3-CO—CH₂Cl 2-Br 4-Br 5-Br 30 —S— 3-CO—CH₂Cl 2-Br 4-Cl 5-Cl 30

1. The use of a compound of formula I:

[wherein: X represents represents a linkage selected from the groupconsisting of —CH═CH—, —CH═CR—, —CR═CR—, —CO—, —O—, —NH—, —NR—, —S—,—SO—, —SO₂—, —CH═N—, —CR═N—, —CH═N(O)—, —CR═N(O)— andr any other atom orgroup of atoms capable of forming a S— or 6-membered heterocyclic ring;Y¹, Y² and Y³ independently represent a substituent selected fromhydrogen and halogen; R¹, R² and R³ are independently represent asubstituent selected from hydrogen, halogen, hydrocarbyl (—R), hydroxyl(—OH), hydrocarbyloxy (—O—R), mercapto (—SH), hydrocarbylthio (—S—R),hydrocarbylsulfinyl (—SO—R), hydrocarbylsulfonyl (—SO₂—R), nitro (—NO₂),amino (—NH₂), hydrocarbylamino (—NHR), bis(hydrocarbyl)amino (—NR₂),hydrocarbylcarbonylamino (—NH—CO—R), cyano (—CN), carbamoyl (—CONH₂),hydrocarbylcarbamoyl (—CONHR), bis(hydrocarbyl)carbamoyl (—CONR₂),carboxyl (—CO₂H), hydrocarbyloxycarbonyl (—CO₂R), formyl (—CHO),hydrocarbylcarbonyl (—COR), hydrocarbylcarbonyloxy (—OCOR), optionallysubstituted heteroaryl and optionally substituted heterocyclic; and thehydrocarbyl group R is a substituent selected from a straight orbranched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl and aralkynyl, which may optionally besubstituted by at least one substituent, selected from those definedabove in relation to R¹, R² and R³]; in the manufacture of a medicamentfor the treatment of a disease mediated by the activation of GSK-3. 2.The use of claim 1, wherein X is selected from —CH═CH—, —CH═CR—,—CR═CR—, —CH═N—, —CR═N—, —O—, —NH—, —NR—, and —S— (the group Rrepresenting C₁₋₆ alkyl or C₆₋₁₀ aryl).
 3. The use of claim 1, wherein Xis selected from —CH═CH—, —CH═CR—, —CR═CR—, —O— and —S— (the group Rrepresenting C₁₋₆ alkyl).
 4. The use of claim 1, wherein X is selectedfrom —CH═CH— and —S—.
 5. The use of claim 1, wherein one or two of Y¹,Y² and Y³ are halogen, and the other two or one are hydrogen.
 6. The useof claim 1, wherein one of Y¹, Y² and Y³ is halogen, and the other twoare hydrogen.
 7. The use of claim 1, wherein one of Y¹, Y² and Y³ ischlorine, bromine or iodine, and the other two are hydrogen.
 8. The useof claim 1, wherein R¹, R² and R³ are independently selected fromhydrogen, halogen, C₁₋₆ alkyl (which may be optionally substituted withone or more substituents selected from halogen, hydroxy, C₁₋₆ alkoxy andcyano), C₆₋₁₀ aryl, optionally substituted C₇₋₁₆ aralkyl, hydroxy, C₁₋₆alkoxy, C₆₋₁₀ aryloxy, C₇₋₁₆ aralkyloxy, C₁₋₆ alkylthio, C₆₋₁₀ arylthio,C₇₋₁₆ aralkylthio, C₁₋₆ alkylsulfinyl, C₆₋₁₀ arylsulfinyl, C₇₋₁₆aralkylsulfinyl, C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₇₋₁₆aralkylsulfonyl, cyano, carboxyl, C₁₋₆ alkyloxycarbonyl, C₇₋₁₁aryloxycarbonyl, C₈₋₁₆ aralkyloxycarbonyl, heteroaryl and C₁₋₃₀aliphatic acyl (which may be optionally substituted with a halogenatom).
 9. The use of claim 1, wherein R¹, R² and R³ are independentlyselected from hydrogen, halogen, C₁₋₆ alkyl (which may be optionallysubstituted with one or more substituents selected from halogen, hydroxyand C₁₋₆ alkoxy), C₁₋₆ alkoxy C₆₋₁₀ aryl, heteroaryl, nitro, amino andC₁₋₂₀ aliphatic acyl (which may be optionally substituted with one ormore substituents selected from halogen, hydroxy and C₁₋₆ alkoxy andcyano).
 10. The use of claim 1, wherein R¹, R² and R³ are independentlyselected from hydrogen, halogen, C₁₋₄ alkyl (which may be optionallysubstituted with one or more halogen atoms), C₁₋₄ alkoxy, C₆₋₁₀ aryl,heteroaryl, nitro, amino and C₂₋₆ aliphatic acyl (which may beoptionally substituted with one or more halogen atoms), provided that atleast one of R¹, R² and R³ are other than hydrogen.
 11. The use of claim1, wherein R¹, R² and R³ are independently selected from hydrogen,chorine, bromine, methyl, ethyl, methoxy, ethoxy, acetyl, chloroacetyl,phenyl, morpholino, nitro, amino, and bromoacetyl, provided that atleast one of R¹, R² and R³ is other than hydrogen.
 12. The use of claim1, wherein R¹, R² and R³ are independently selected from hydrogen,chloro, bromo, iodo, methyl, methoxy, acetyl, phenyl, morpholino, nitro,amino, and chloroacetyl, provided that at least one of R¹, R² and R³ isother than hydrogen.
 13. The use of claim 1, selected from the followingtable: comp. —X— COCY¹Y²Y³ R¹ R² R³ 1 —S— 3-COCH₂Cl 2-Br 4-Cl 5-Cl 2 —S—2-COCH₂Cl 4-Cl 5-Cl H 3 —S— 2-COCH₂Cl 4-Br H H 4 —S— 3-COCH₂Cl 4-Cl H H5 —S— 3-COCH₂Cl 2-Br 4-Br 5-Br 6 —S— 3-COCH₂Cl 2-Cl 5-Cl H 7 —S—2-COCH₂Cl 5-Cl H H 8 —S— 2-COCH₂Cl 5-Br H H 9 —S— 2-COCH₂Cl 4-COCH₂Cl HH 10 —S— 2-COCH₂Cl H H H 11 —S— 2-COCH₂Cl 4-COCH₂Cl 5-CH₃ 12 —S—2-COCH₂Cl 5-CH₃ H H 13 —S— 3-COCH₂Cl 2-CH₃ 5-CH₃ H 14 —S— 2-COCH₂Cl 4-Br5-Br H 15 —S— 2-COCH₂Cl 3-Br 4-Br H 16 —S— 2-COCH₂Cl 3-CH₃ 4-COCH₂Cl 17—S— 2-COCH₂Cl 4-CH₃ H H 18 —S— 2-COCH₂Cl 3-CH₃ H H 19 —S— 2-COCH₂Cl5-COCH₃ H H 20 —S— 2-COCH₂Cl 4-COCH₃ H H 21 —S— 2-COCH₂Br 3-Br 4-Br H 22—S— 2-COCH₂Br 4-Br 5-Br H 23 —S— 2-COCH₂Br 5-Br H H 24 —CH═CH— COCH₂Cl4-Cl H H 25 —CH═CH— COCH₂Cl H H H 26 —CH═CH— COCH₂Br 2-Br 4-Br 6-Br 27—CH═CH— COCH₂Cl 3-Br 4-Br H 28 —CH═CH— COCH₂Cl 4-Br H H 29 —CH═CH—COCH₂Cl 4-Cl H H 30 —CH═CH— COCH₂Cl H H H 31 —CH═CH— COCH₂Cl 4-CH₃ H H32 —CH═CH— COCH₂Cl 4-OCH₃ H H 33 —CH═CH— COCH₂Cl 4-Ph H H 34 —CH═CH—COCHBrCl 4-Cl H H 35 —CH═CH— COCHBrCl H H H 36 —CH═CH— COCHBr₂ H H H 37—CH═CH— COCHBr₂ 4-Br H H 38 —CH═CH— COCHBr₂ 4-CN H H 39 —CH═CH— COCHBr₂4-CN H H 40 —CH═CH— COCHBr₂ 4-CF₃ H H 41 —CH═CH— COCHBr₂ 4-CF₃ H H 42—CH═CH— COCHBr₂ 4-Morpholine H H 43 —CH═CH— COCHBr₂ 3-CN H H 44 —CH═CH—COCHBr₂ 3-CN H H 45 —CH═CH— COCHBr₂ 4-I H H 46 —CH═CH— COCHBr₂ 4-N0₂ H H47 —CH═CH— COCHBr₂ 3-Br 4-NH₂ 5-Br 48 —CH═CH— COCH₂I 4-Br H H


14. The use of claim 1, wherein the disease is Aizheimer's disease. 15.The use of claim 1, wherein the disease is non-dependent insulindiabetes mellitus.
 16. The use of claim 1 in the manufacture of amedicament for the treatment of a hyperproliferative disease.
 17. Theuse of claim 16, wherein the hyperproliferative disease is selected fromcancer, displasias and metaplasia of different tissues, psoriasis,arteriosclerosis and restenosis.
 18. A compound of formula I:

wherein: X represents —CH═CH—, —CH═CR—, —CR═CR—, —CO—, —O—, —NH—, —NR—,—S—, —SO—, —SO₂—, —CH═N—, —CR═N—, —CH═N(O)—, —CR═N(O)— or any other atomor group of atoms capable of forming a S— or 6-membered heterocyclicring; Y¹, Y² and Y³ independently represent hydrogen or halogen; R¹, R²and R³ are independently represent hydrogen, halogen, hydrocarbyl (—R),hydroxyl (—OH), hydrocarbyloxy (—O—R), mercapto (—SH), hydrocarbylthio(—S—R), hydrocarbylsulfinyl (—SO—R), hydrocarbylsulfonyl (—SO₂—R), nitro(—NO₂), amino (—NH₂), hydrocarbylamino (—NHR), bis(hydrocarbyl)amino(—NR₂), hydrocarbylcarbonylamino (—NH—CO—R), cyano (—CN), carbamoyl(—CONH₂), hydrocarbylcarbamoyl (—CONHR), bis(hydrocarbyl)carbamoyl(—CONR₂), carboxyl (—CO₂H), hydrocarbyloxycarbonyl (—CO₂R), formyl(—CHO), hydrocarbylcarbonyl (—COR), hydrocarbylcarbonyloxy (—OCOR),optionally substituted heteroaryl or optionally substitutedheterocyclic; and the hydrocarbyl group R is a straight or branchedchain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl,aralkyl, aralkenyl and aralkynyl, which may optionally be substituted byone or more substituents, selected from those defined above in relationto R¹, R² and R³.
 19. A pharmaceutical preparation containing as activeingredient a compound according to claim
 18. 20. A compound according toclaim 18 for use as a medicament.
 21. A method of treatment of a diseasemediated by the activation of GSK-3, the method comprising administeringan effective amount of a compound according to claim 18.